Reciprocal effects of mTOR inhibitors on pro-survival proteins dictate therapeutic responses in tuberous sclerosis complex

Molly C. McNamara, Aaron M. Hosios, Margaret E. Torrence, Ting Zhao, Cameron Fraser, Meghan Wilkinson, David J. Kwiatkowski, Elizabeth P. Henske, Chin Lee Wu, Kristopher A. Sarosiek, Alexander J. Valvezan, Brendan D. Manning

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

mTORC1 is aberrantly activated in cancer and in the genetic tumor syndrome tuberous sclerosis complex (TSC), which is caused by loss-of-function mutations in the TSC complex, a negative regulator of mTORC1. Clinically approved mTORC1 inhibitors, such as rapamycin, elicit a cytostatic effect that fails to eliminate tumors and is rapidly reversible. We sought to determine the effects of mTORC1 on the core regulators of intrinsic apoptosis. In TSC2-deficient cells and tumors, we find that mTORC1 inhibitors shift cellular dependence from MCL-1 to BCL-2 and BCL-XL for survival, thereby altering susceptibility to BH3 mimetics that target specific pro-survival BCL-2 proteins. The BCL-2/BCL-XL inhibitor ABT-263 synergizes with rapamycin to induce apoptosis in TSC-deficient cells and in a mouse tumor model of TSC, resulting in a more complete and durable response. These data expose a therapeutic vulnerability in regulation of the apoptotic machinery downstream of mTORC1 that promotes a cytotoxic response to rapamycin.

Original languageEnglish (US)
Article number105458
JournaliScience
Volume25
Issue number11
DOIs
StatePublished - Nov 18 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Biological sciences
  • Cancer
  • Cell biology
  • Molecular biology

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